Doxorubicin degradation in cardiomyocytes

Area of Science:

• Biochemistry
• Pharmacology
• Cardiology

Background:

• Doxorubicin (DOX) is an effective antitumor drug, but its use is limited by severe cardiotoxicity.
• DOX cardiotoxicity is linked to cardiac DOX levels and reactive oxygen species (ROS) generation.
• Previous studies indicated myoglobin could degrade DOX, but a lack of specific inhibitors prevented pharmacological evaluation.

Purpose of the Study:

• To investigate the role of DOX oxidative degradation in its cardiotoxicity.
• To evaluate tert-butoxycarbonyl-alanine (TBCA) as a potential inhibitor of DOX degradation.
• To explore the implications of DOX degradation for managing cardiotoxicity.

Main Methods:

• In vitro assessment of TBCA's effect on DOX degradation by hydrogen peroxide-activated oxyferrous myoglobin.
• In vitro and cellular studies using H9c2 cardiomyocytes to assess TBCA's impact on DOX uptake, efflux, ROS generation, and toxicity.
• Evaluation of TBCA's effect on the toxicity of DOX analogs with varying degradation susceptibility.

Main Results:

• TBCA inhibited in vitro DOX degradation induced by activated myoglobin.
• In cardiomyocytes, TBCA increased intracellular DOX levels, ROS production, and DOX-induced toxicity.
• TBCA exacerbated the toxicity of a degradation-prone analog (daunorubicin) but had minimal effect on a resistant analog (aclarubicin).
• In vitro oxidized DOX showed reduced cardiotoxicity.

Conclusions:

• TBCA increases DOX cardiotoxicity by inhibiting its oxidative degradation to less toxic products.
• Oxidative degradation of DOX represents a potential salvage pathway to mitigate DOX-induced cardiotoxicity.
• Findings suggest therapeutic strategies targeting DOX metabolism could manage cardiotoxicity, particularly at clinically relevant low DOX concentrations.